Diazabicyclooctane derivatives having selective 5-HT1Dalpha agonist activity

ABSTRACT

A class of 3-substituted 3,7-diazabicyclo[3.3.0]octane derivatives, further substituted at the 7-position by an optionally substituted alkenyl, alkynyl, arylcarbonyl, aryl-alkyl or heteroaryl-alkyl moiety, are selective agonists of 5-HT 1  -like receptors, being potent agonists of the human 5-HT 1D α  receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT 1D α  receptor subtype relative to the 5-HT 1D β  subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT 1D  receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT 1D  receptor agonists.

The present invention relates to a class of substituted3,7-diazabicyclo[3.3.0]octane derivatives which act on5-hydroxytryptamine (5-HT) receptors, being selective agonists ofso-called "5-HT₁ -like" receptors. They are therefore useful in thetreatment of clinical conditions for which a selective agonist of thesereceptors is indicated.

It has been known for some time that 5-HT₁ -like receptor agonists whichexhibit selective vasoconstrictor activity are of use in the treatmentof migraine (see, for example, A. Doenicke et al., The Lancet, 1988,Vol. 1, 1309-11; and W. Feniuk and P. P. A. Humphrey, Drug DevelopmentResearch, 1992, 26, 235-240).

The human 5-HT₁ -like or 5-HT_(1D) receptor has recently been shown bymolecular cloning techniques to exist in two distinct subtypes. Thesesubtypes have been termed 5-HT_(1D).sbsb.α (or 5-HT_(1D-1)) and5-HT_(1D).sbsb.β (or 5-HT_(1D-2)), and their amino acid sequences aredisclosed and claimed in WO-A-91/17174.

The 5-HT_(1D).sbsb.α receptor subtype in humans is believed to reside onsensory terminals in the dura mater. Stimulation of the 5-HT_(1D).sbsb.αsubtype inhibits the release of inflammatory neuropeptides which arethought to contribute to the headache pain of migraine. The human5-HT_(1D).sbsb.β receptor subtype, meanwhile, is located predominantlyon the blood vessels and in the brain, and hence may play a part inmediating constriction of cerebral and coronary arteries, as well as CNSeffects.

Administration of the prototypical 5-HT_(1D) agonist sumatriptan(GR43175) to humans is known to give rise at therapeutic doses tocertain adverse cardiovascular events (see, for example, F. Willett etal., Br. Med. J., 1992, 304, 1415, J. P. Ottervanger et al., The Lancet,1993, 341. 861-2; and D. N. Bateman, The Lancet, 1993, 341, 221-4).Since sumatriptan barely discriminates between the human5-HT_(1D).sbsb.α and 5-HT_(1D).sbsb.β receptor subtypes (cf.WO-A-91/17174, Table 1), and since it is the blood vessels with whichthe 5-HT_(1D).sbsb.β subtype is most closely associated, it is believedthat the cardiovascular side-effects observed with sumatriptan can beattributed to stimulation of the 5-HT_(1D).sbsb.β receptor subtype. Itis accordingly considered (cf. G. W. Rebeck et al., Proc. Natl. Acad.Sci. USA, 1994, 91, 3666-9) that compounds which can interactselectively with the 5-HT_(1D).sbsb.α receptor subtype, whilst having aless pronounced action at the 5-HT_(1D).sbsb.β subtype, might be freefrom, or at any rate less prone to, the undesirable cardiovascular andother side-effects associated with non-subtype-selective 5-HT_(1D)receptor agonists, whilst at the same time maintaining a beneficiallevel of anti-migraine activity.

The compounds of the present invention, being selective 5-HT₁ -likereceptor agonists, are accordingly of benefit in the treatment ofmigraine and associated conditions, e.g. cluster headache, chronicparoxysmal hemicrania, headache associated with vascular disorders,tension headache and paediatric migraine. In particular, the compoundsaccording to this invention are potent agonists of the human5-HT_(1D).sbsb.α receptor subtype. Moreover, the compounds in accordancewith this invention have been found to possess at least a 10-foldselective affinity for the 5-HT_(1D).sbsb.α receptor subtype relative tothe 5-HT_(1D).sbsb.β subtype, and they can therefore be expected tomanifest fewer side-effects than those associated withnon-subtype-selective 5-HT_(1D) receptor agonists.

Several distinct classes of substituted five-membered heteroaromaticcompounds are described in published European patent applications0438230, 0494774 and 0497512, and published International patentapplications 93/18029, 94/02477 and 94/03446. The compounds describedtherein are stated to be agonists of 5-HT₁ -like receptors, andaccordingly to be of particular use in the treatment of migraine andassociated conditions. None of these publications, however, disclosesnor even suggests the 3,7-diazabicyclo[3.3.0]octane derivatives providedby the present invention.

In EP-A-0548813 is described a series of alkoxypyridin-4yl andalkoxypyrimidin-4-yl derivatives of indol-3-ylalkylpiperazines which arealleged to provide treatment of vascular or vascular-related headaches,including migraine. There is, however, no disclosure nor any -suggestionin EP-A-0548813 of replacing the substituted piperazine moiety with adifferently substituted 3,7-diazabicyclo[3.3.0]octane moiety.

WO-A-91/18897 describes a class of tryptamine derivatives substituted byvarious five-membered rings, which are stated to be specific --to aparticular type of "5-HT₁ -like" receptor and thus to be effectiveagents for the treatment of clinical conditions, particularly migraine,requiring --this activity. However, WO-A-91/18897 neither discloses norsuggests the 3,7-diazabicyclo[3.3.0]octane derivatives provided by thepresent invention.

Moreover, nowhere in the prior art mentioned above is there anydisclosure of a subtype-selective 5-HT_(1D) receptor agonist having a5-HT_(1D).sbsb.α receptor binding affinity (IC₅₀) below 50 nM and atleast a 10-fold selective affinity for the 5-HT_(1D).sbsb.α receptorsubtype relative to the 5-HT_(1D).sbsb.β subtype.

The compounds according to the present invention are subtype-selective5-HT_(1D) receptor agonists having a human 5-HT_(1D).sbsb.α receptorbinding affinity (IC₅₀) below 50 nM, typically below 10 nM andpreferably below 1 nM; and at least a 10-fold selective affinity,typically at least a 50-fold selective affinity and preferably at leasta 100-fold selective affinity, for the human 5-HT_(1D).sbsb.α receptorsubtype relative to the 5-HT_(1D).sbsb.β subtype.

The present invention provides a compound of formula I, or a salt orprodrug thereof: ##STR1## wherein Z represents hydrogen, halogen, cyano,nitro, trifluoromethyl, --OR⁵, --OCOR⁵, --OCONR⁵ R⁶, --OCH₂ CN, --OCH₂CONR⁵ R⁶, --SR⁵, --SOR⁵, --SO₂ R⁵, --SO₂ NR⁵ R⁶, --NR⁵ R⁶, --NR⁵ COR⁶,--NR⁵ CO₂ R⁶, --NR⁵ SO₂ R⁶, --COR⁵, --CO₂ R⁵, --CONR⁵ R⁶, or a group offormula (a), (b), (c) or (d): ##STR2## in which the asterisk * denotes achiral centre; or Z represents an optionally substituted five-memberedheteroaromatic ring selected from furan, thiophene, pyrrole, oxazole,thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole,thiadiazole, triazole and tetrazole;

X represents oxygen, sulphur, --NH-- or methylene;

Y represents oxygen or sulphur;

E represents a chemical bond or a straight or branched alkylene chaincontaining from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to6 carbon atoms, optionally substituted in any position by a hydroxygroup;

T represents nitrogen or CH;

U represents nitrogen or C--R² ;

V represents oxygen, sulphur or N--R³ ;

R¹ represents C₃₋₆ alkenyl, C₃₋₆ alkynyl, arylcarbonyl, aryl(C₁₋₆)alkylor heteroaryl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted;

R², R³ and R⁴ independently represent hydrogen or C₁₋₆ alkyl; and

R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl, trifluoromethyl,phenyl, methylphenyl, or an optionally substituted aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl group.

Where Z in the compounds of formula I above represents a five-memberedheteroaromatic ring, this ring may be optionally substituted by one or,where possible, two substituents. As will be appreciated, where Zrepresents an oxadiazole, thiadiazole or tetrazole ring, only onesubstituent will be possible; otherwise, one or two optionalsubstituents may be accommodated around the five-membered heteroaromaticring Z. Examples of suitable substituents on the five-memberedheteroaromatic ring Z include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,heteroaryl, heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, halogen, cyano and trifluoromethyl.

The group R¹ may be optionally substituted by one or more substituents,as also may the groups R⁵ or R⁶ where these represent aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl. Where R¹, R⁵ or R⁶ represents aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any optional substitution will suitably be on thearyl or heteroaryl moiety thereof, although substitution on the alkylmoiety thereof is an alternative possibility. Examples of optionalsubstituents thereon include halogen, cyano, trifluoromethyl, triazolyl,tetrazolyl, C₁₋₆ alkyl-tetrazolyl, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₂₋₆ alkoxycarbonyl, C₂₋₆ alkylcarbonyl, C₁₋₆ alkylsulphonyl,arylsulphonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylaminomethyl, C₂₋₆ alkylcarbonylamino, arylcarbonylamino,C₂₋₆ alkoxycarbonylamino, N-(C₁₋₆)alkyl-N-(C₂₋₆)alkoxycarbonylamino,C₁₋₆ alkylsulphonylamino, arylsulphonylamino, C₁₋₆alkylsulphonylaminomethyl, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, di(C₁₋₆)alkylaminocarbonylamino, mono- ordiarylaminocarbonylamino, pyrrolidinylcarbonylamino,piperidinylcarbonylamino, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆ alkylaminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, aminosulphonylmethyl, C₁₋₆alkylaminosulphonylmethyl and di(C₁₋₆)alkylaminosulphonylmethyl.

As used herein, the expression "C₁₋₆ alkyl" includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyland tert-butyl. Derived expressions such as "C₁₋₆ alkoxy", "C₁₋₆alkylthio" and "C₁₋₆ alkylamino" are to be construed accordingly.

The expression "C₂₋₆ alkenyl" as used herein refers to straight-chainedand branched alkenyl groups containing from 2 to 6 carbon atoms. Typicalexamples include vinyl, allyl, dimethylallyl and butenyl groups.

The expression "C₂₋₆ alkynyl" as used herein refers to straight-chainedand branched alkynyl groups containing from 2 to 6 carbon atoms. Typicalexamples include ethynyl and propargyl groups.

Typical C₃₋₇ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

Typical aryl groups include phenyl and naphthyl.

A typical arylcarbonyl group is benzoyl.

The expression "aryl(C₁₋₆)alkyl" as used herein includes benzyl,phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolylgroups.

The expression "heteroaryl(C₁₋₆)alkyl" as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl,oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethylimidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl,thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl,tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl andisoquinolinylmethyl.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoicacid, oxalic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts. e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g. quaternary ammonium salts.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. For example,the compounds of formula I above wherein Z represents a group of formula(b) or (c) have a chiral centre denoted by the asterisk *, which mayaccordingly be in the (R) or (S) configuration. It is to be understoodthat all such isomers and mixtures thereof in any proportion areencompassed within the scope of the present invention.

In particular, the ring junction between the fused five-membered ringsin the 3,7-diazabicyclo[3.3.0]octane moiety depicted in formula I ispreferably in the cis configuration.

Where E and Q, which may be the same or different, represent straight orbranched alkylene chains, these may be, for example, methylene,ethylene, 1-methylethylene, propylene, 2-methylpropylene or butylene. Inaddition, the alkylene chain Q may be substituted in any position by ahydroxy group giving rise, for example, to a 2-hydroxypropylene or2-hydroxymethyl-propylene chain Q. Moreover, E may represent a chemicalbond such that the moiety Z is attached directly to the central fusedbicyclic heteroaromatic ring system containing the variables T, U and V.

Suitably, E represents a chemical bond or a methylene linkage.

Representative alkylene chains for Q include propylene, butylene,2-hydroxypropylene and 2-hydroxymethyl-propylene, especially propylene.

The compound of formula I in accordance with the present invention issuitably an indole, benzofuran or benzthiophene derivative of formulaIA, an indazole derivative of formula IB, or a pyrrolo[2,3-c]-pyridinederivative of formula IC: ##STR3## wherein Z, E, Q, V, R¹, R² and R³ areas defined above. Preferably, the compounds according to the inventionare indole or pyrrolo[2,3-c]pyridine 10 derivatives of formula ID:##STR4## wherein Z, E, Q, T, R¹, R² and R³ are as defined above, inparticular wherein R² and R³ are both hydrogen.

Suitable values for the substituent R¹ include allyl, dimethylallyl,butenyl, propargyl, benzoyl, benzyl, phenylethyl, furylmethyl,thienylmethyl, imidazolylmethyl and pyridinylmethyl, any of which groupsmay be optionally substituted by one or more substituents selectedtypically from halogen, cyano, triazolyl, tetrazolyl, C₁₋₆alkyl-tetrazolyl, C₁₋₆ alkoxy, amino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylaminomethyl, C₂₋₆ alkylcarbonylamino, C₂₋₆alkoxycarbonylamino, N-(C₁₋₆)alkyl-N-(C₂₋₆ )alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, aminocarbonylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl and C₁₋₆alkylaminosulphonylmethyl.

Representative values of R¹ include allyl, dimethylallyl, butenyl,propargyl, benzoyl, benzyl, fluorobenzyl, difluorobenzyl, cyanobenzyl,tetrazolyl-benzyl, methyltetrazolyl-benzyl, methoxybenzyl, aminobenzyl,dimethylaminomethyl-benzyl, acetylamino-benzyl, aminocarbonyl-benzyl,methylaminocarbonyl-benzyl, dimethylaminocarbonyl-benzyl,aminosulphonyl-benzyl, phenylethyl, fluoro-phenylethyl,difluoro-phenylethyl, cyano-phenylethyl, triazolyl-phenylethyl,amino-phenylethyl, dimethylamino-phenylethyl, acetylamino-phenylethyl,methoxycarbonylamino-phenylethyl,(N-methyl-N-methoxycarbonyl)amino-phenylethyl,aminocarbonylamino-phenylethyl, furylmethyl, thienylmethyl,imidazolylmethyl, pyridinylmethyl and amino-pyridinylmethyl.

Particular values of R¹ include benzoyl, benzyl, acetylamino-phenylethyland pyridinylmethyl.

Suitably, R² and R³ independently represent hydrogen or methyl,especially hydrogen.

Suitably, R⁴ represents hydrogen or methyl, especially hydrogen.

Suitably, R⁵ and R⁶ are independently selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl,phenyl, methylphenyl (especially 4-methylphenyl), benzyl and phenethyl.

Suitably, the substituent Z represents hydrogen, fluoro, cyano, hydroxy,methoxy, ethoxy, benzyloxy, methylamino-carbonyloxy, cyano-methoxy,aminocarbonyl-methoxy, methylsulphonyl, aminosulphonyl,N-methylamino-sulphonyl, N,N-dimethylamino-sulphonyl, amino,formylamino, acetylamino, trifluoromethyl-carbonylamino,benzyloxy-carbonylamino, methyl-sulphonylamino, ethyl-sulphonylamino,methylphenyl-sulphonylamino, N-methyl-(N-methylsulphonyl)-amino,N-methyl-(N-ethylsulphonyl)-amino,N-methyl-(N-trifluoromethylsulphonyl)-amino,N-ethyl-(N-methylsulphonyl)-amino, N-benzyl-(N-methylsulphonyl)-amino,N-benzyl-(N-ethylsulphonyl)-amino, acetyl, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,propylaminocarbonyl, butylaminocarbonyl, benzylaminocarbonyl orphenethyl-aminocarbonyl; or a group of formula (a), (b), (c) or (d) asdefined above; or an optionally substituted five-membered heteroaromaticring as specified above.

In a particular embodiment, Z represents --SO₂ NR⁵ R⁶ in which R⁵ and R⁶are as defined above. In a subset of this embodiment, R⁵ and R⁶independently represent hydrogen or C₁₋₆ alkyl, especially hydrogen ormethyl. Particular values of Z in this context include aminosulphonyl,N-methylamino-sulphonyl and N,N-dimethylamino-sulphonyl, especiallyN-methylamino-sulphonyl.

In another embodiment, Z represents a group of formula (b) in which R⁴is hydrogen or methyl. In a subset of this embodiment, X and Y bothrepresent oxygen. In a particular aspect of this subset, the chiralcentre denoted by the asterisk * is in the (S) configuration.

When the group Z represents an optionally substituted five-memberedheteroaromatic ring, this is suitably a 1.3-oxazole, 1,3-thiazole.imidazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole ring.Preferably, the ring is a 1,3-oxazole, 1,3-thiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole or 1,2,4-triazole ring, in particular a1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl moiety.

Suitably, the five-membered heteroaromatic ring Z is unsubstituted.Examples of optional substituents which may typically be attached to themoiety Z include methyl, ethyl, benzyl and amino.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof: ##STR5## wherein m is zero, 1, 2 or 3;

p is 1, 2 or 3;

Q¹ represents a straight or branched alkylene chain containing from 2 to5 carbon atoms, optionally substituted in any position by a hydroxygroup;

T represents nitrogen or CH;

A represents nitrogen or CH;

B represents nitrogen or C--R⁸ ;

R⁷ and R⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₇ cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,heteroaryl, heteroaryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino,01-6 alkylamino, di(C₁₋₆)alkylamino, halogen, cyano or trifluoromethyl;and

W represents a group of formula (Wa), (Wb) or (Wc): ##STR6## in which W¹represents CH or nitrogen;

W² represents oxygen, sulphur, NH or N-methyl; and

R⁹ represents hydrogen, halogen, cyano, trifluoromethyl, triazolyl,tetrazolyl, C₁₋₆ alkyl-tetrazolyl, C₁₋₆ alkoxy, C₂₋₆ alkylcarbonyl,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, di(C₁₋₆)alkylaminomethyl,C₂₋₆ alkylcarbonylamino, C₁₋₆ alkylsulphonylamino, aminocarbonylamino,C₁₋₆ alkylaminocarbonyl, aminosulphonyl or C₁₋₆alkylaminosulphonylmethyl.

Suitably, Q¹ represents a straight or branched 3 or 4 carbon alkylenechain, optionally substituted in any position by a hydroxy group.Particular alkylene chains for Q¹ include propylene, butylene.2-hydroxypropylene and 2-(hydroxymethyl)-propylene, especiallypropylene.

Particular values of R⁷ and R⁸ include hydrogen, methyl, ethyl, benzyland amino, especially hydrogen.

Particular values of R⁹ include hydrogen, fluoro, cyano, triazolyl,tetrazolyl, methyl-tetrazolyl, methoxy, amino, dimethylaminomethyl,acetylamino, aminocarbonylamino, methylaminocarbonyl and aminosulphonyl,especially hydrogen or acetylamino.

Another sub-class of compounds according to the invention is representedby the compounds of formula IIB, and salts and prodrugs thereof:##STR7## wherein m, p, Q¹, T and W are as defined with reference toformula IIA above; and

R⁵ and R⁶ are as defined with reference to formula I above.

Particular values of R⁵ and R⁶ in relation to formula IIB above includehydrogen and C₁₋₆ alkyl, especially hydrogen or methyl. Suitably, one ofR⁵ and R⁶ represents hydrogen and the other represents hydrogen ormethyl.

A further sub-class of compounds according to the invention isrepresented by the compounds of formula IIC, and salts and prodrugsthereof: ##STR8## wherein the asterisk * denotes a chiral centre; m, p,Q¹, T and W are as defined with reference to formula IIA above; and

R⁴ and Y are as defined with reference to formula I above.

Particular values of R⁴ in relation to formula IIC include hydrogen andmethyl, especially hydrogen.

Preferably, Y in formula IIC is oxygen.

Preferably, the chiral centre denoted by the asterisk * in formula IICis in the (S) configuration.

Specific compounds within the scope of the present invention include:

3-benzyl-7-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-cis-3,7-diazabicyclo[3.3.0]octane;

3-(pyridin-3-yl)methyl-7-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-cis-3,7-diazabicyclo[3.3.0]octane;

3-[2-(4-(acetylamino)phenyl)ethyl]-7-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-cis-3,7-diazabicyclo[3.3.0]octane;

3-benzoyl-7-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-cis-3,7-diazabicyclo[3.3.0]octane;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of migraine, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds according to the invention may be prepared by a processwhich comprises attachment of the R¹ moiety to a compound of formulaIII: ##STR9## wherein Z, E, Q, T, U and V are as defined above; byconventional means including N-alkylation and N-aroylation.

Attachment of the R¹ moiety to the compounds of formula III mayconveniently be effected by standard alkylation techniques. One examplethereof comprises treatment with an alkenyl halide such as4-bromobut-1-ene, 4-bromo-2-methylbut-2-ene or allyl bromide, an alkynylhalide such as propargyl bromide, or an aryl(Ci-c)alkyl orheteroaryl(C₁₋₆)alkyl halide such as2-bromo-1-[4-(acetylamino)phenyl]-ethane, typically in the presence ofsodium carbonate and sodium iodide, in a suitable solvent such as1,2-dimethoxyethane.

Alternatively, the R¹ moiety may conveniently be attached by reductivealkylation, which may be accomplished in a single step, or as a two-stepprocedure. The single-step approach suitably comprises treating therequired compound of formula III as defined above with the appropriatealdehyde, e.g. benzaldehyde, pyridine carboxaldehyde. furfuraldehyde orthiophene carboxaldehyde, in the presence of a reducing agent such assodium cyanoborohydride. In a typical two-step procedure. for thepreparation of a compound of formula I wherein R¹ corresponds to a groupof formula --CH₂ R¹¹, a carboxylic acid derivative of formula R¹¹ --CO₂H is condensed with the required compound of formula III, suitably inthe presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and 1-hydroxybenzotriazole hydrate, to afford a compoundcorresponding to formula I wherein R¹ represents --COR¹¹ ; the carbonylgroup thereof can then be reduced, for example by treatment withdiisobutylaluminium hydride, and the required compound of formula Ithereby obtained.

Where R¹ represents an arylcarbonyl moiety, this group may beconveniently attached by standard aroylation techniques. One examplethereof comprises treatment of compound III with an aroyl halide, e.g.benzoyl chloride, typically in the presence of triethylamine, in asuitable solvent such as dichloromethane.

The compounds of formula III above wherein T represents CH, U representsC-R² and V represents N--R³, corresponding to the indole derivatives offormula ID as defined above wherein T represents CH and R¹ is hydrogen,may be prepared by a process which comprises reacting a --compound offormula IV: ##STR10## wherein Z and E are as defined above; with acompound of formula V, or a carbonyl-protected form thereof: ##STR11##wherein R² and Q are as defined above, and R^(p) represents anamino-protecting group; followed, where required, by N-alkylation bystandard methods to introduce the moiety R³ ; with subsequent removal ofthe amino-protecting group R^(p).

The reaction between compounds IV and V, which is an example of thewell-known Fischer indole synthesis, is suitably carried out by heatingthe reagents together under mildly acidic conditions, e.g. 4% sulphuricacid at reflux.

Suitable carbonyl-protected forms of the compounds of formula V includethe dimethyl acetal or ketal derivatives.

The protecting group R^(p) in the compounds of formula V is suitably acarbamoyl moiety such as tert-butoxycarbonyl (BOC), which canconveniently be removed as necessary by treatment under mildly acidicconditions. Indeed, the acidic conditions of the Fischer indolesynthesis reaction will generally suffice to remove the BOC group.

The Fischer reaction between compounds IV and V may be carried out in asingle step, or may proceed via an initial non-cyclising step at a lowertemperature to give an intermediate of formula VI: ##STR12## wherein Z,E, Q, R² and R^(p) are as defined above; followed by cyclisation using asuitable reagent, e.g. a polyphosphate ester.

The intermediates of formula V, or carbonyl-protected forms thereof, maybe prepared by reacting a compound of formula VII, or acarbonyl-protected form thereof, with a compound of formula VIII:##STR13## wherein Q, R² and R^(p) are as defined above, and L¹represents a suitable leaving group.

The leaving group L¹ is suitably a halogen atom, e.g. chlorine orbromine.

Where L¹ represents a halogen atom, the reaction between compounds VIIand VIII is conveniently effected by stirring the reactants under basicconditions in a suitable solvent, for example sodium carbonate in1,2-dimethoxyethane, typically in the presence of catalytic sodiumiodide.

The compounds according to the invention wherein T represents CH, Urepresents C--R² and V represents N--R³ --i.e. the indole derivatives offormula ID as defined above wherein T represents CH--may alternativelybe prepared by a process which comprises reacting a compound of formulaIT as defined above with a compound of formula IX, or acarbonyl-protected form thereof: ##STR14## wherein Q, R¹ and R² are asdefined above; under conditions analogous to those described above forthe reaction between compounds IV and V; followed, where required, byN-alkylation by standard methods to introduce the moiety R³.

As for the compounds of formula V, suitable carbonyl-protected forms ofthe compounds of formula IX include the dimethyl acetal or ketalderivatives. Where the alkylene chain Q is substituted by a hydroxygroup, this group may condense with the carbonyl moiety in compounds Vand IX, whereby the carbonyl moiety is protected in the form of a cyclichemiacetal.

As with that between compounds IV and V, the Fischer reaction betweencompounds IV and IX may be carried out in a single step, or may proceedvia an initial non-cyclising step at a lower temperature to give anintermediate of formula X: ##STR15## wherein Z, E, Q, R¹ and R² are asdefined above; followed by cyclisation using a suitable reagent, e.g. apolyphosphate ester.

The intermediates of formula IX, or carbonyl-protected forms thereof,may be prepared by reacting a compound of formula VII as defined above,or a carbonyl-protected form thereof, with a compound of formula XI:##STR16## wherein R¹ is as defined above; under conditions analogous tothose described above for the reaction between compounds VII and VIII.

In an alternative procedure, the compounds of formula III above may beprepared by a process which comprises reacting a compound of formulaVIII as defined above with a compound of formula XII: ##STR17## whereinZ, E, Q, T, U and V are as defined above, and L² represents a suitableleaving group; followed by removal of the amino-protecting group R^(p).

Similarly, the compounds of formula I as defined above may be preparedby a process which comprises reacting a compound of formula XI asdefined above with a compound of formula XII as defined above.

The leaving group L² is suitably an alkylsulphonyloxy orarylsulphonyloxy group, e.g. methanesulphonyloxy (mesyloxy) orp-toluenesulphonyloxy (tosyloxy).

Where L² represents an alkylsulphonyloxy or arylsulphonyloxy group, thereaction between compound XII and compound VIII or XI is convenientlycarried out in a suitable solvent such as 1,2-dimethoxyethane orisopropyl alcohol, optionally in the presence of a cosolvent such asacetonitrile, typically in the presence of a base such as sodiumcarbonate or potassium carbonate, and optionally with the addition ofsodium iodide.

In a representative embodiment, the compounds of formula XII wherein Tand U both represent CH, V represents NH, Q represents a propylene chainand L² represents a mesyloxy or tosyloxy group may be prepared byreacting 3,4-dihydro-2H-pyran with a compound of formula IV as definedabove or a salt thereof, under a variant of the Fischer reactionconditions as described above for the reaction between compounds IV andV; followed by mesylation or tosylation of the 3-hydroxypropyl-indolederivative thereby obtained, typically by treatment with mesyl chlorideor tosyl chloride under standard conditions.

The Fischer reaction with 3,4-dihydro-2H-pyran is suitably brought aboutby heating the hydrazine derivative IV or an acid addition salt thereof,typically the hydrochloride salt, in an inert solvent such as dioxan,advantageously in the presence of a mineral acid such as hydrochloricacid or a Lewis acid such as zinc chloride, at the reflux temperature ofthe solvent.

In a further procedure, the compounds of formula III above wherein Trepresents CH, U represents nitrogen and V represents N--R³,corresponding to the indazole derivatives of formula IB as defined abovewherein R¹ is hydrogen, may be prepared by a process which comprisescyclising a compound of formula XIII: ##STR18## wherein Z, E, Q andR^(p) are as defined above, and D¹ represents a readily displaceablegroup; followed, where required, by N-alkylation by standard methods tointroduce the moiety R³ ; with subsequent removal of theamino-protecting group R^(p).

Similarly, the compounds of formula I wherein T represents CH, Urepresents nitrogen and V represents N--R³ --i.e. the indazolederivatives of formula IB as defined above--may be prepared by a processwhich comprises cyclising a compound of formula XIV: ##STR19## in whichZ, E, Q, R¹ and D¹ are as defined above; followed, where required, byN-alkylation by standard methods to introduce the moiety R³.

The cyclisation of compounds XIII and XIV is conveniently achieved in asuitable organic solvent at an elevated temperature, for example in amixture of m-xylene and 2,6-lutidine at a temperature in the region of140° C.

The readily displaceable group D¹ in the compounds of formula XIII andXIV suitably represents a C₁₋₄ alkanoyloxy group, preferably acetoxy.Where D¹ represents acetoxy, the desired compound of formula XIII or XIVmay be conveniently prepared by treating a carbonyl compound of formulaXV: ##STR20## wherein Z, E and Q are as defined above, and R^(x)corresponds to the group R¹ as defined above, or R^(x) represents anamino-protecting group as defined for R^(p) ; or a protected derivativethereof, preferably the N-formyl protected derivative, withhydroxylamine hydrochloride, advantageously in pyridine at the refluxtemperature of the solvent: followed by acetylation with aceticanhydride, advantageously in the presence of a catalytic quantity of4-dimethylaminopyridine, in dichloromethane at room temperature.

The N-formyl protected derivatives of the intermediates of formula XVmay conveniently be prepared by ozonolysis of the corresponding indolederivative of formula XVI: ##STR21## wherein Z, E, Q and R^(x) are asdefined above; followed by a reductive work-up, advantageously usingdimethylsulphide.

The indole derivatives of formula XVI may be prepared by methodsanalogous to those described in the accompanying Examples, or byprocedures well known from the art.

In a still further procedure, the compounds of formula III above whereinT represents CH, U represents C--R² and V represents oxygen or sulphur,corresponding to the benzofuran or benzthiophene derivatives of formulaIA wherein V is oxygen or sulphur respectively and R¹ is hydrogen, maybe prepared by a process which comprises cyclising a compound of formulaXVII: ##STR22## wherein Z, E, Q, R² and R^(p) are as defined above, andV¹ represents oxygen or sulphur; followed by removal of theamino-protecting group R^(p).

Similarly, the compounds of formula I wherein T represents CH, Urepresents C--R² and V represents oxygen or sulphur--i.e. the benzofuranor benzthiophene derivatives of formula IA above--may be prepared by aprocess which comprises cyclising a compound of formula XVIII: ##STR23##wherein Z, E, Q, R¹, R² and V¹ are as defined above.

The cyclisation of compounds XVII and XVIII is conveniently effected byusing polyphosphoric acid or a polyphosphate ester, advantageously at anelevated temperature.

The compounds of formula XVII and XVIII may be prepared by reacting acompound of formula XIX with a compound of formula XX: ##STR24## whereinZ, E, Q, R², V¹ and R^(x) are as defined above, and Hal represents ahalogen atom.

The reaction is conveniently effected in the presence of a base such assodium hydroxide.

The hydroxy and mercapto derivatives of formula XIX may be prepared by avariety of methods which will be readily apparent to those skilled inthe art. One such method is described in EP-A-0497512.

In a yet further procedure, the compounds of formula III above may beprepared by a process which comprises reducing a compound of formulaXXI: ##STR25## wherein Z, E, T, U, V and R^(p) are as defined above, and--Q² --CH₂ --corresponds to the moiety Q as defined above; withsubsequent removal of the amino-protecting group R^(p).

Similarly, the compounds according to the invention may be prepared by aprocess which comprises reducing a compound of formula XXII: ##STR26##wherein Z, E, T, U, V, R¹ and Q² are as defined above.

The reduction of compounds XXI and XXII is conveniently effected bytreating the appropriate compound with a reducing agent such as lithiumaluminium hydride in an appropriate solvent, e.g. diethyl ether ortetrahydrofuran, or mixtures thereof.

The compounds of formulae XXI and XXII above may suitably be prepared byreacting a compound of formula XXIII with the appropriate compound offormula XXIV: ##STR27## wherein Z, E, T, U, V, R^(x) and Q² are asdefined above, and J represents a reactive carboxylate moiety.

Suitable values for the reactive carboxylate moiety J include esters,for example C₁₋₄ alkyl esters; acid anhydrides, for example mixedanhydrides with C₁₋₄ alkanoic acids; acid halides, for example acidchlorides; and acylimidazoles.

By way of example, the intermediates of formula XXIII above wherein J isan acid chloride moiety may be prepared by treating the correspondingcarboxylic acid derivative with thionyl chloride in toluene. Similarly,the intermediates of formula XXII wherein J is an acylimidazole moietymay be prepared by treating the corresponding carboxylic acid derivativewith 1,1'-carbonyldiimiidazole. Alternatively, the reactive carboxylatemoiety J may be obtained by treating the corresponding compound whereinJ is carboxy with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and 1-hydroxybenzotriazole hydrate, optionally in thepresence of triethylamine: the resulting activated carboxylateintermediate may then suitably be reacted in situ with the requiredcompound of formula XXIV.

The hydrazine derivatives of formula IV above may be prepared by methodsanalogous to those described in EP-A-0438230, EP-A-0497512, EP-A-0548813and WO-A-91/18897.

Where they are not commercially available, the starting materials offormula VII, VIII, XI, XX, XXIII and XXIV may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard procedures well known from the art.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art. For example, a compound of formula I wherein R¹ is benzylinitially obtained may be converted by catalytic hydrogenation to thecorresponding compound of formula III, which in turn may be convertedinto a further compound of formula I using standard N-alkylationtechniques as described above. Furthermore, a compound of formula Iinitially obtained wherein the R¹ moiety is substituted by nitro orcyano may be converted by catalytic hydrogenation to the correspondingamino- or aminomethyl-substituted compound respectively. Additionally, acompound of formula I wherein the R¹ moiety is substituted by hydroxy,possibly obtained by lithium aluminium hydride reduction of a precursoralkoxycarbonyl derivative, may be mesylated under standard conditions,and the mesyl group subsequently displaced by an amino moiety bytreatment with the desired amine in a sealed tube at an elevatedtemperature. The amine derivative resulting from any of these proceduresmay then, for example, be N-acylated using the appropriate acyl halide,e.g. acetyl chloride; or aminocarbonylated, using potassium isocyanate,to the corresponding urea derivative; or converted to a1,2,4-triazol-4-yl derivative using N,N-dimethylformamide azine; orreductively alkylated by treatment with the appropriate aldehyde orketone in the presence of sodium cyanoborohydride. If desired, the aminederivative may also be carbamoylated by treatment with the requisitealkyl chloroformate. A compound of formula I initially obtained whereinthe R¹ moiety is substituted by cyano may be converted, by treatmentwith sodium azide, to the corresponding tetrazole derivative, which inturn may be alkylated on the tetrazole ring by treatment with an alkylhalide under standard conditions. By way of additional illustration, acompound of formula I initially obtained wherein the R¹ moiety issubstituted by an alkoxycarbonyl moiety may be saponified, by treatmentwith an alkali metal hydroxide, to the corresponding carboxy-substitutedcompound, which in turn may be converted to an amide derivative bytreatment with the appropriate amine, advantageously in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole. Moreover, a compound of formula I wherein R³ ishydrogen initially obtained may be converted into a compound of formulaI wherein R³ represents C₁₋₆ alkyl by standard alkylation techniques,for example by treatment with an alkyl iodide, e.g. methyl iodide,typically under basic conditions, e.g. sodium hydride indimethylformamide, or triethylamine in acetonitrile.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compounds may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with the present invention potently andselectively bind to the 5-HT_(1D).sbsb.α receptor subtype, inhibitforskolin-stimulated adenylyl cyclase activity, and stimulate [³⁵S]-GTPγS binding to membranes from clonal cell lines expressing humancloned receptors.

5-HT_(1D).sbsb.α /5-HT_(1D).sbsb.β Radioligand Binding

Chinese hamster ovary (CHO) clonal cell lines expressing the human5-HT_(1D).sbsb.α and 5-HT_(1D).sbsb.β receptors were harvested in PBSand homogenised in ice cold 50 mM Tris-HCl (pH 7.7 at room temperature)with a Kinematica polytron and centrifuged at 48,000 g at 4° C. for 11min. The pellet was then resuspended in 50 mM Tris-HCl followed by a 10min incubation at 37° C. Finally the tissue was recentrifuged at 48,000g, 4° C. for 11 min and the pellet resuspended, in assay buffer(composition in mM: Tris-HCl 50, pargyline 0.01, CaCl₂ 4; ascorbate0.1%; pH 7.7 at room temperature) to give the required volumeimmediately prior to use (0.2 mg protein/ml). Incubations were carriedout for 30 min at 37° C. in the presence of 0.02-150 nM [³ H]-5-HT forsaturation studies or 2-5 nM [³ H]-5-HT for displacement studies. Thefinal assay volume was 1 ml. 5-HT (10 μM) was used to definenon-specific binding. The reaction was initiated by the addition ofmembrane and was terminated by rapid filtration through Whatman GF/Bfilters (presoaked in 0.3% PEI/0.5% Triton X) followed by 2×4 mlwashings with 50 mM Tris-HCl. The radioactive filters were then countedon a LKB beta or a Wallac beta plate counter. Binding parameters weredetermined by non-linear, least squares regression analysis using aniterative curve fitting routine, from which IC₅₀ (the molarconcentration of compound necessary to inhibit binding by 50%) valuescould be calculated for each test compound. The IC₅₀ values for bindingto the 5-HT_(1D).sbsb.α receptor subtype obtained for the compounds ofthe accompanying Examples were below 50 nM in each case. Furthermore,the compounds of the accompanying Examples were all found to possess aselective affinity for the 5-HT_(1D).sbsb.α receptor subtype of at least10-fold relative to the 5-HT_(1D).sbsb.β subtype.

5-HT_(1D).sbsb.α /5-HT_(1D).sbsb.β Adenylyl Cyclase Assay

Studies were performed essentially as described in J. Pharmacol. Exp.Ther., 1986, 238, 248. CHO clonal cell lines expressing the human cloned5-HT_(1D).sbsb.α and 5-HT_(1D).sbsb.β receptors were harvested in PBSand homogenised, using a motor driven teflon/glass homogeniser, in icecold Tris HCl-EGTA buffer (composition in mM: Tris HCl 10, EGTA 1, pH8.0 at room temperature) and incubated on ice for 30-60 min. The tissuewas then centrifuged at 20,000 g for 20 min at 4° C., the supernatantdiscarded and the pellet resuspended in Tris HCl-EDTA buffer(composition in mM: Tris HCl 50, EDTA 5, pH 7.6 at room temperature)just prior to assay. The adenylyl cyclase activity was determined bymeasuring the conversion of α-[³³ P]-ATP to [³³ P]-cyclic AMP. A 10 μlaliquot of the membrane suspension was incubated, for 10-15 min, in afinal volume of 50 μl, at 30° C., with or without forskolin (10 μM), inthe presence or absence of test compound. The incubation bufferconsisted of 50 mM Tris HCl (pH 7.6 at room temperature), 100 mM NaCl,30 μl GTP. 50 μM cyclic AMP, 1 mM dithiothreitol, 1 mM ATP, 5 mM MgCl₂,1 mM EGTA, 1 mM 3-isobutyl-1-methylxanthine, 3.5 mM creatininephosphate, 0.2 mg/ml creatine phosphokinase, 0.5-1 μCi α-[³³ P]-ATP and1 nCi [³ H]-cyclic AMP. The incubation was initiated by the addition ofmembrane, 5 following a 5 min preincubation at 30° C., and wasterminated by the addition of 100 μl SDS (composition in mM: sodiumlauryl sulphate 2%, ATP 45, cyclic AMP 1.3, pH 7.5 at room temperature).The ATP and cyclic AMP were separated on a double column chromatographysystem (Anal. Biochem., 1974, 58, 541). Functional parameters weredetermined using a least squares curve fitting programme ALLFIT (Am. J.Physiol., 1978, 235, E97) from which E_(max) (maximal effect) and EC₅₀(the molar concentration of compound necessary to inhibit the maximaleffect by 50%) values were obtained for each test compound. Of thosecompounds which were tested in this assay, the EC₅₀ values for the5-HT_(1D).sbsb.α receptor obtained for the compounds of the accompanyingExamples were below 500 nM in each case. Moreover, the compounds of theaccompanying Examples which were tested were all found to possess atleast a 10-fold selectivity for the 5-HT_(1D).sbsb.α receptor subtyperelative to the 5-HT_(1D).sbsb.α subtype.

5-HT_(1D).sbsb.α /5-HT_(1D).sbsb.β GTPγS Binding

Studies were performed essentially as described in Br. J. Pharmacol.,1993, 109, 1120. CHO clonal cell lines expressing the human cloned5-HT_(1D).sbsb.α and 5-HT_(1D).sbsb.β receptors were harvested in PBSand homogenised using a Kinematica polytron in ice cold 20 mM HEPEScontaining 10 mM EDTA, pH 7.4 at room temperature. The membranes werethen centrifuged at 40,000 g, 4° C. for 15 min. The pellet was thenresuspended in ice cold 20 mM HEPES containing 0.1 mM EDTA, pH 7.4 atroom temperature and recentrifuged at 40,000 g, 4° C. for 15-25 minutes.The membranes were then resuspended in assay buffer (composition in mM:HEPES 20, NaCl 100, MgCl₂ 10, pargyline 0.01; ascorbate 0.1%; pH 7.4 atroom temperature) at a concentration of 40 μg protein/ml for the5-HT_(1D).sbsb.α receptor transfected cells and 40-50 μg protein/ml forthe 5-HT_(1D).sbsb.β receptor transfected cells. The membrane suspensionwas then incubated, in a volume of 1 ml, with GDP (100 μM for5-HT_(1D).sbsb.α receptor transfected cells, 30 μM for the5-HT_(1D).sbsb.β receptor transfected cells) and test compound at 30° C.for 20 min and then transferred to ice for a further 15 min. [³⁵S]-GTPγS was then added at a final concentration of 100 pM and thesamples incubated for 30 min at 30° C. The reaction was initiated by theaddition of membrane and was terminated by rapid filtration throughWhatman GF/B filters and washed with 5 ml water. The radioactive filterswere then counted on a LKB beta counter. Functional parameters weredetermined by a non-linear, least squares regression analysis using aniterative curve fitting routine, from which E_(max) (maximal effect) andEC₅₀ (the molar concentration of compound necessary to inhibit themaximal effect by 50%) values were obtained for each test compound. Ofthose compounds which were tested in this assay, the EC₅₀ values for the5-HT_(1D).sbsb.α receptor obtained for the compounds of the accompanyingExamples were below 500 nM in each case. Moreover, the compounds of theaccompanying Examples which were tested were all found to possess atleast a 10-fold selectivity for the 5-HT_(1D).sbsb.α receptor subtyperelative to the 5-HT_(1D).sbsb.α subtype.

EXAMPLE 1

cis-3-[3-(5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)propyl]-5-(1,2,4-triazol-4-yl)-1H-indole.1.5 Hydrogen Oxalate. 0.5 Hydrate. 0.1 Etherate

Intermediate 1: Benzyl-methoxymethyl-trimethylsilanylmethyl-amine

N-Benzyltrimethylsilylmethylamine (10 g, 52 mmol) was added dropwiseover 30 minutes to a stirred mixture of aqueous formaldehyde (38%, 5.0ml, 69 mmol) and methanol (2.5 ml, 61 mmol) at 0° C. Upon completeaddition the reaction was allowed to warm slowly to room temperature,then stirred at this temperature for 16 h. The mixture was diluted withether and the two layers separated. The organic layer was dried (Na₂SO₄), filtered and evaporated to give the title amine (11 g, 90%) as aclear colourless oil. δ (250 MHz, CDCl₃)-0.01 (9H, s, SiMe₃), 2.14 (2H,s), 3.19 (3H, s, OMe), 3.71 (2H, s), 3.95 (2H, s), 7.16-7.32 (5H, m,Ar--H). This material was used without further purification.

Intermediate 2:cis-2,5-Dibenzyl-tetrahydro-pyrrolo[3,4c]pyrrole-1,3-dione

Trifluoroacetic acid (1.1 M in CH₂ Cl₂, 3 ml, 3.0 mmol) was addeddropwise to a stirred solution ofbenzylmethoxymethyl-trimethylsilanylmethyl-amine (9.0 g, 37.9 mmol) andN-benzylmaleimide (5.5 g, 29.3 mmol) in dry dichloromethane (60 ml) at0° C. under nitrogen. Upon complete addition, the reaction was stirredat 0° C. for 15 minutes, then at room temperature for 45 minutes. Themixture was transferred to a separating funnel and washed with saturatedaqueous sodium hydrogen carbonate (x1) and water (x1). The organic layerwas dried (Na₂ SO₄), filtered and evaporated. The residue was purifiedby chromatography on silica gel eluting with 40% ethyl acetate/petroleumether to give the title pyrrolo-pyrrole (9.2 g, 98%) as a colourlesssolid. δ (360 MHz, d₆ -DMSO) 2.30-2.36 (2H, m), 3.07 (2H, d, J=9.8 Hz),3.28-3.36 (2H, m), 3.54 (2H, s), 4.58 (2H, s), 7.16-7.36 (10H, m,Ar--H).

Intermediate 3: cis-2-Benzyl-tetrahydro-pyrrolo[3.4c]pyrrole-1.3-dione

A mixture of 2,5-dibenzyl-tetrahydro-pyrrolo[3,4c]pyrrole-1,3-dione (8.8g, 27.5 mmol), ammonium formate (8.8 g, 140 mmol), 5N HCl (5.6 ml, 28mmol) and 10% Pd/C (800 mg) in methanol (240 ml) was heated at refluxunder nitrogen for 1 hour. Upon cooling, the catalyst was removed byfiltration through celite, washing with methanol. The filtrate wasevaporated and the residue was partitioned between dichloromethane andsaturated aqueous sodium hydrogen carbonate. The aqueous was furtherextracted with dichloromethane (x2). The combined extracts were washedwith brine (x1), dried (Na₂ SO₄), filtered and evaporated. The residuewas purified by chromatography on silica gel eluting with CH₂ Cl₂/MeOH/NH₃ (95:5:0.5→91:8:1) to give the title amine (6.4 g,˜100%) as aclear colourless oil. δ (360 MHz, CDCl₃) 2.95-3.04 (2H, m), 3.20-3.25(2H, m), 3.49 (2H, d, J=11.5 Hz), 4.64 (2H, s, CH₂ Ph), 7.24-7.36 (5H,m, Ar--H).

Intermediate 4: cis-2-Benzyl-octahydro-pyrrolo[3.4-c]pyrrole

Lithium aluminium hydride (1M in THF, 85 ml, 85 mmol) was added slowlyto a stirred solution of2-benzyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione (6.4 g, 27.8 mmol)in dry tetrahydrofuran (60 ml) at room temperature under nitrogen. Uponcomplete addition, the mixture was stirred and heated at 70° C. for 16h. The mixture was then cooled to 0° C. and carefully quenched withwater (3.2 ml), followed by 4N sodium hydroxide (3.2 ml) and water (4.5ml). The mixture was filtered, washing with ethyl acetate. The filtratewas evaporated and the residue was purified by chromatography on silicagel, eluting with CH₂ Cl₂ /MeOH/NH₃ (40:8:1→30:8:1) to give the titleamine (4.5 g, 80%) as a clear oil. ¹ H NMR δ (360 MHz, CDCl₃) 2.24-2.28(2H, m), 2.42 (1H, s), 2.56-2.64 (4H, m), 2.68 (1H, dd, J=11.5. 2.4 Hz),2.77-2.83 (2H, m), 3.44 (2H, s, CH₂ Ph), 7.13-7.30 (5H, m, Ar--H). ¹³ CNMR δ (90.5 MHz, CDCl₃) 43.6 (CH), 54.4 (CH₂), 59.9 (CH₂), 60.8 (CH₂),126.8 (CH), 128.2 (CH), 128.8 (CH), 139.3 (C).

Intermediate 5:cis-2-Benzyl-5-(5.5-dimethoxy-pentyl)octahydro-pyrrolo[3,4-c]pyrrole

A mixture of 2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (2.1 g, 10.4mmol), 5-chloropentanal-dimethylacetal (1.75 g, 10.5 mmol), sodiumiodide (1.71 g, 11.4 mmol) and sodium carbonate (1.21 g, 11.4 mmol) indry 1,2-dimethoxyethane (30 ml) was stirred and heated at reflux undernitrogen and protected from light for 16 h. The volatiles were thenremoved in vacuo and the residue partitioned between ethyl acetate andsaturated aqueous potassium carbonate. The aqueous was further extractedwith ethyl acetate (x2). The combined extracts were dried (Na₂ SO₄),filtered and evaporated. The residue was then purified by chromatographyon silica gel, eluting with CH₂ Cl₂ /MeOH/NH₃ (95:5:0.5) to give thetitle acetal (2.8 g, 81%) as a clear colourless oil. δ (250 MHz, CDCl₃)1.35-1.65 (6H, m), 2.35-2.95 (12H, m), 3.32 (6H, s, (OMe)₂); 3.48 (2H,s, CH₂ Ph), 7.23-7.33 (5H, m, Ar--H).

cis-3-[3-(5-Benzyl-hexahydro-pyrrolo[3.4-c]pyrrol-2-yl)propyl]-5-(1,2,4-triazol-4-yl)-1H-indole.1.5 Hydrogen oxalate. 0.5 Hydrate. 0.1 Etherate

4-(1,2,4-Triazol-4-yl)phenylhydrazine (EP581538) (1.48 g, 8.4 mmol) wasadded in one portion to a stirred solution of2-benzyl-5-(5,5-dimethoxypentyl)octahydro-pyrrolo[3,4-c]pyrrole (2.8 g,8.4 mmol) in 4% sulphuric acid (50 ml) at room temperature. After 30minutes at room temperature the mixture was heated to reflux undernitrogen for 72h. The reaction was then cooled to 0° C. and quenchedwith solid potassium carbonate. The aqueous was then extracted within-butanol (x4). The combined extracts were evaporated and the residuepurified by chromatography on silica gel, eluting with CH₂ Cl₂ /MeOH/NH₃(94:5:1→91:8:1→89:10:1) to give the title indole (1.3 g, 35%) as ayellow foam. An analytically pure sample was obtained by furtherchromatography of a small portion of the above sample on silica gel,eluting with Et₂ O/EtOH/NH₃ (40:10:1) to give the title indole (150 mg)as a colourless solid. The 1.5 hydrogen oxalate. 0.5 hydrate. 0.1etherate was prepared (Et₂ O/MeOH): mp 149-153° C. (Found: C, 61.12; H,6.25; N, 14.07. C₂₆ H₃₀ N₆.1.5(C₂ H₂ O₄).0.5(H₂ O). 0.1(C₄ H₁₀ O)requires C, 61.16; H, 6.24; N, 14.26%). δ (360 MHz, d₆ -DMSO) 1.98-2.08(2H, m), 2.50-2.60 (1H, m), 2.70-2.82 (5H, m), 2.86-3.00 (5H, m),3.06-3.14 (2H, m), 3.38-3.50 (1H, br m), 3.76 (2H, br s, CH₂ Ph),7.26-7.38 (7H, m, Ar--H), 7.51 (1H, d, J=8.6 Hz, Ar--H), 7.82 (1H, d,J=2.0 Hz, Ar--H), 9.02 (2H, s, Triazole-H), 11.19 (1H, br s, N--H).

EXAMPLE 2

cis-N-(4-(2-(5-(3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)ethyl)phenyl)acetamide.2 Hydrogen oxalate. 0.75 Hydrate

Intermediate 1:cis-3-(3-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)pyropyl)-5-(1,2,4-triazol-4-yl)-1H-indole

A mixture of3-(3-(5-benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-propyl)-5-(1,2,4-triazol-4-yl)-1H-indole(1.3 g, 3.0 mmol), ammonium formate (950 mg, 15.1 mmol), 5N HCl (600 μl,3.0 mmol) and 10% Pd/C (200 mg) in methanol (30 ml) was stirred andheated at reflux for 90 minutes. Upon cooling, the reaction mixture wasfiltered through celite, washing with methanol. The filtrate wasevaporated and the residue partitioned between saturated aqueouspotassium carbonate and n--butanol. The aqueous was further extractedwith 7z-butanol (x3). The combined extracts were evaporated and theresidue was purified by chromatography on neutral alumina (grade III),eluting with 5% MeOH/CH₂ Cl₂, then CH₂ Cl₂ /MeOH/NH₃ (95:5:0.5), to givethe title amine (905 mg, 90%) as a foam. δ (360 MHz, CDCl₃) 1.78-1.86(4H, m), 2.21-2.23 (2H, m), 2.34-2.39 (2H, m), 2.56-2.88 (9H, m),7.05-7.08 (2H, m, Ar--H), 7.40 (1H, d, J=8.6 Hz, Ar--H), 7.49 (1H, d,J=2.0 Hz, Ar--H), 8.40 (2H, s, Triazole-H), 8.58 (1H, br s, N--H).

cis-N-(4-(2-(5-(3-(5-(1,2,4-Triazol-4-yl)-1H-indol-3-yl)propyl)hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)ethyl)phenyl)acetamide.2 Hydrogen oxalate. 0.75 Hydrate

Sodium iodide (98 mg, 0.65 mmol) was added to a mixture of3-(3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)propyl)-5-(1,2,4-triazol-4-yl)-1H-indole(200 mg, 0.59 mmol), sodium carbonate (95 mg, 0.90 mmol) andN-(4-(2-bromoethyl)phenyl)acetamide (158 mg, 0.65 mmol) in dry1,2-dimethoxyethane (5 ml) at room temperature under nitrogen. Themixture was then stirred and heated to reflux, protected from light, for16 h. Upon cooling, the volatiles were removed in vacuo and the residuewas partitioned between dichloromethane and water. The aqueous wasfurther extracted with dichloromethane (x2). The combined extracts weredried (Na₂ SO₄), filtered and evaporated. The residue was purified bychromatography on silica gel, eluting with CH₂ Cl₂ /MeOH/NH₃(60:8:1→50:8:1) to give the title indole (88 mg, 30%) as a foam. The bishydrogen oxalate. 0.75 hydrate was prepared (Et₂ O/MeOH): mp 151-155° C.(Found: C, 57.43; H, 6.26; N, 14.35. C₂₉ H₃₅ N₇ O.2(C₂ H₂ O₄).0.75(H₂ O)requires C, 57.34; H, 5.91; N, 14.18%). δ (360 MHz, d₆ -DMSO) 1.94-2.02(5H, m, includes NC(O)CH₃), 2.7-3.3 (18H, m), 7.16 (2H, d, J=8.5 Hz,Ar--H), 7.30-7.36 (2H, m, Ar--H), 7.48-7.52 (3H, m, Ar--H), 7.81 (1H, s,Ar--H), 9.03 (2H, s, Triazole-H), 9.89 (1H, s, N--H), 11.17 (1H, s,N--H).

EXAMPLE 3

cis-Phenyl-(5-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)-hexahydropyrrolo[3.4-c]pyrrol-2-yl)methanone.2 Hydrogen oxalate. 0.5 Hydrate. 0.15 Etherate

Benzoyl chloride (57 μl, 0.49 mmol) was added to a stirred solution of3-(3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)propyl)-5-(1,2,4-triazol-4-yl)-1H-indole(150 mg, 0.45 mmol) and triethylamine (125 μl, 0.90 mmol) in drydichloromethane (5 ml) at 0° C. under nitrogen. The reaction was allowedto warm slowly to room temperature and then stirred at this temperaturefor 72 h. The reaction was diluted with dichloromethane, then washedwith saturated aqueous sodium hydrogen carbonate (x1). The organic layerwas dried (Na₂ SO₄), filtered and evaporated. The residue was purifiedby chromatography on silica gel, eluting with CH₂ Cl₂ /MeOH/NH₃(80:8:1→60:8:1) to give the title indole (138 mg, 70%) as a foam. Thebis hydrogen oxalate. 0.5 hydrate. 0.15 etherate was prepared (Et₂O/MeOH): (Found: C, 57.64; H, 5.39; N, 12.75. C₂₆ H₂₈ N₆ O.2(C₂ H₂O₄)₂.0.5(H₂ O).0.15(C₄ H₁₀ O) requires C, 57.36; H, 5.43; N, 13.12%). δ(360 MHz, d₆ -DMSO) 1.96-2.08 (2H, m); 2.76-2.82 (2H, m), 3.00-3.20 (5H,m), 3.4-3.7 (5H, br m); 7.30-7.33 (2H, m, Ar--H), 7.42-7.52 (6H, m,Ar--H), 7.80 (1H, d, J=1.9 Hz, Ar--H), 9.00 (2H, s, Triazole-H), 11.18(1H, br s, N--H).

I claim:
 1. A compound of formula I, or a salt thereof: ##STR28##wherein Z represents 1,2,4-triazole optionally substituted with C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, aryl,aryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, halogen, cyano or trifluoromethyl, wherein arylrepresents phenyl or naphthyl; ##STR29## E represents a chemical bond ora straight or branched alkylene chain containing from 1 to 4 carbonatoms;Q represents a straight or branched alkylene chain containing from1 to 6 carbon atoms, optionally substituted in any position by a hydroxygroup; T represents CH; U represents C--R² ; V represents N--R³ ; R¹represents C₃₋₆ alkenyl, C₃₋₆ alkynyl, arylcarbonyl, or aryl(C₁₋₆)alkyl,wherein aryl is phenyl or naphthyl, any of which groups may beoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁₋₆ alkoxy, amino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylaminomethyl, C₂₋₆ alkylcarbonylamino, C₂₋₆alkoxycarbonylamino, N-(C₁₋₆)alkyl-N-(C₂₋₆)alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, aminocarbonylamino, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, C₁₋₆alkylaminosulphonylmethyl; and R² and R³ independently representhydrogen or C₁₋₆ alkyl.
 2. A compound as claimed in claim 1 representedby formula IIA, or a salt thereof: ##STR30## wherein m is zero, 1, 2or3;p is 1, 2or 3; Q¹ represents a straight or branched alkylene chaincontaining from 2 to 5 carbon atoms, optionally substituted in anyposition by a hydroxy group; T represents CH; A represents nitrogen andB represents C--R⁸, or B represents nitrogen and A represents CH; R⁷ andR⁸ independently represent hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, aryl, aryl(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, halogen, cyano or trifluoromethyl,wherein aryl represents phenyl or naphthyl; and W represents a group offormula (Wa): ##STR31## in which W¹ represents CH; and R⁹ representshydrogen, halogen, cyano, trifluoromethyl, C₁₋₆ alkoxy, C₂₋₆alkylcarbonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylaminomethyl, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulphonylamino, aminocarbonylamino, C₁₋₆ alkylaminocarbonyl,aminosulphonyl or C₁₋₆ alkylaminosulphonylmethyl.
 3. A compound selectedfrom:3-benzyl-7-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-cis-3,7-diazabicyclo[3.3.0]octane;3-[2-(4-(acetylamino)phenyl)ethyl]-7-[3-(5-(1,2,4-triazol-4yl)-1H-indol-3-yl)propyl]cis-3,7-diazabicyclo[3.3.0]octane;3-benzoyl-7-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-cis-3,7-diazabicyclo[3.3.0]octane;ora salt thereof.
 4. A method for the treatment of migraine and associatedconditions, which method comprises administering to a patient in need ofsuch treatment an effective amount of a compound as claimed in claim 1.